Ste-Justine Hospital Research Centre, Department of Obstetrics and Gynecology, Universite de Montreal, 3175, chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada; Department of Pharmacology and Physiology, Universite de Montreal, 2900 Edouard-Montpetit Boulevard, Montreal, Quebec, H3T 1J4, Canada.
Ste-Justine Hospital Research Centre, Department of Obstetrics and Gynecology, Universite de Montreal, 3175, chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada; Department of Microbiology, Infectiology, and Immunology, Universite de Montreal, 2900 Edouard-Montpetit Boulevard, Montreal, Quebec, H3T 1J4, Canada.
Placenta. 2019 Jan;75:9-15. doi: 10.1016/j.placenta.2018.11.006. Epub 2018 Nov 22.
Inflammation is an important cause of placental dysfunction often associated with pregnancy complications. One well-known cause of inflammation is infection, through conserved "pathogen-associated molecular patterns" (PAMPs). Endogenous inducers of inflammation, known as "damage-associated molecular patterns" (DAMPs), have also been associated with pathological pregnancies and could contribute to the observed placental inflammation. Although both stimuli (i.e. PAMPs/DAMPs) can induce inflammation, they have yet to be studied together to compare their inflammatory effects on the placenta.
We used a model of term placental explants to compare the effects of a classical PAMP, bacterial lipopolysaccharide (LPS), and a DAMP, the pro-inflammatory cytokine interleukin (IL)-1. Gene and protein expression of several cytokines were analysed by qPCR and ELISAs and immunohistochemistry performed to study placental resident immune cells and apoptosis.
LPS induced pro-inflammatory mediators (IL-6, IL-1β/α, TNF-α) whereas IL-1β induced only IL-6. Furthermore, LPS but not IL-1 exposure, led to elevated IL-10 and IL-1Ra secretion. Blocking the IL-1 signalling pathway abrogated the pro-inflammatory actions of LPS, whilst anti-inflammatory effects were preserved. The number of CD45 immune cells was elevated in explants treated with LPS only. A subpopulation of CD45 cells were positive for PCNA indicating proliferation of tissue resident macrophages.
We conclude that LPS, a classical PAMP, and IL-1, a DAMP, have shared and distinct actions with pro-inflammatory effects mediated through IL-1 but anti-inflammatory actions having a distinct pathway. Identification of an inflammatory mediator (i.e. IL-1) common to multiple stimuli could be a therapeutic target to preserve the placenta.
炎症是胎盘功能障碍的一个重要原因，常与妊娠并发症有关。炎症的一个众所周知的原因是感染，通过保守的“病原体相关分子模式”（PAMPs）。内源性炎症诱导物，称为“损伤相关分子模式”（DAMPs），也与病理性妊娠有关，并可能导致观察到的胎盘炎症。尽管这两种刺激物（即 PAMPs/DAMPs）都可以诱导炎症，但它们尚未一起研究，以比较它们对胎盘的炎症作用。
我们使用足月胎盘外植体模型比较了经典的 PAMP 细菌脂多糖（LPS）和促炎细胞因子白细胞介素（IL）-1 的 DAMP。通过 qPCR 和 ELISA 分析几种细胞因子的基因和蛋白表达，并进行免疫组织化学染色以研究胎盘固有免疫细胞和细胞凋亡。
LPS 诱导促炎介质（IL-6、IL-1β/α、TNF-α），而 IL-1β仅诱导 IL-6。此外，LPS 暴露而非 IL-1 暴露导致 IL-10 和 IL-1Ra 分泌增加。阻断 IL-1 信号通路可消除 LPS 的促炎作用，而抗炎作用得以保留。仅用 LPS 处理的外植体中 CD45 免疫细胞数量增加。CD45 细胞的一个亚群对 PCNA 呈阳性，表明组织驻留巨噬细胞增殖。
我们得出结论，LPS，一种经典的 PAMP，和 IL-1，一种 DAMP，具有共同和独特的作用，通过 IL-1 介导促炎作用，但抗炎作用具有独特的途径。鉴定一种与多种刺激物共同的炎症介质（即 IL-1）可能是一种保留胎盘的治疗靶点。
